Anita Pawar

University of Chicago, Chicago, IL, United States

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Publications (6)26.05 Total impact

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    ABSTRACT: Recurrent apnea with intermittent hypoxia is a major clinical problem in preterm infants. Recent studies, although limited, showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension, suggesting that apnea of prematurity predisposes to autonomic dysfunction in adulthood. Here, we demonstrate that adult rats that were exposed to intermittent hypoxia as neonates exhibit exaggerated responses to hypoxia by the carotid body and adrenal chromaffin cells, which regulate cardio-respiratory function, resulting in irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity was associated with elevated oxidative stress, decreased expression of genes encoding antioxidant enzymes, and increased expression of pro-oxidant enzymes. Decreased expression of the Sod2 gene, which encodes the antioxidant enzyme superoxide dismutase 2, was associated with DNA hypermethylation of a single CpG dinucleotide close to the transcription start site. Treating neonatal rats with decitabine, an inhibitor of DNA methylation, during intermittent hypoxia exposure prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction. These findings implicate a hitherto uncharacterized role for DNA methylation in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.
    Proceedings of the National Academy of Sciences 02/2012; 109(7):2515-20. · 9.81 Impact Factor
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    ABSTRACT: We recently reported that adrenomedullary chromaffin cells (AMC) from neonatal rats treated with intermittent hypoxia (IH) exhibit enhanced catecholamine secretion by hypoxia (Souvannakitti D, Kumar GK, Fox A, Prabhakar NR. J Neurophysiol 101: 2837-2846, 2009). In the present study, we examined whether neonatal IH also facilitate AMC responses to nicotine, a potent stimulus to chromaffin cells. Experiments were performed on rats exposed to either IH (15-s hypoxia-5-min normoxia; 8 h/day) or to room air (normoxia; controls) from ages postnatal day 0 (P0) to P5. Quantitative RT-PCR analysis revealed expression of mRNAs alpha(3-), alpha(5-), alpha(7-), and beta(2-) and beta(4-)nicotinic acetylcholine receptor (nAChR) subunits in adrenal medullae from control P5 rats. Nicotine-elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) in AMC and nAChR antagonists prevented this response, suggesting that nAChRs are functional in neonatal AMC. In IH-treated rats, nAChR mRNAs were downregulated in AMC, which resulted in a markedly attenuated nicotine-evoked elevation in [Ca(2+)](i) and subsequent catecholamine secretion. Systemic administration of antioxidant prevented IH-evoked downregulation of nAChR expression and function. P35 rats treated with neonatal IH exhibited reduced nAChR mRNA expression in adrenal medullae, attenuated AMC responses to nicotine, and impaired neurogenic catecholamine secretion. Thus the response to neonatal IH lasts for at least 30 days. These observations demonstrate that neonatal IH downregulates nAChR expression and function in AMC via reactive oxygen species signaling, and the effects of neonatal IH persist at least into juvenile life, leading to impaired neurogenic catecholamine secretion from AMC.
    AJP Cell Physiology 08/2010; 299(2):C381-8. · 3.71 Impact Factor
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    ABSTRACT: We recently reported that adrenomedullary chromaffin cells (AMC) from neonatal rats treated with intermittent hypoxia (IH) exhibit enhanced catecholamine secretion by hypoxia. In the present study we examined whether neonatal IH also facilitate AMC responses to nicotine, a potent stimulus to chromaffin cells. Experiments were performed on rats exposed to either IH (15s hypoxia-5min normoxia; 8h/day) or to room air (normoxia; controls) from ages P0-P5. Quantitative RT-PCR analysis revealed expression of mRNAs encoding alpha3, alpha5, alpha7 and beta2 and beta4 nAChR subunits in adrenal medullae from control P5 rats. Nicotine elevated [Ca(2+)](i) in AMC and nAChR antagonists prevented this response suggesting that nAChRs are functional in neonatal AMC. In IH treated rats, nAChR mRNAs were down-regulated in AMC which resulted in a markedly attenuated nicotine-evoked elevation in [Ca(2+)](i) and subsequent catecholamine secretion. Systemic administration of anti-oxidant prevented IH-evoked down-regulation of nAChR expression and function. P35 rats treated with neonatal IH exhibited reduced nAChR mRNA expression in adrenal medullae, attenuated AMC responses to nicotine and impaired neurogenic catecholamine secretion. Thus the response to neonatal IH lasts for at least 30 days. These observations demonstrate that neonatal IH down-regulates nAChR expression and function in AMC via reactive oxygen species signaling and the effects of neonatal IH persist at least into juvenile life leading to impaired neurogenic catecholamine secretion from AMC.
    AJP Cell Physiology 05/2010; · 3.71 Impact Factor
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    ABSTRACT: We previously reported that intermittent hypoxia (IH) augments hypoxic sensory response (HSR) and increases the number of glomus cells in neonatal carotid bodies. In the present study, we tested the hypothesis that recruitment of endothelin-1 (ET-1) signaling by reactive oxygen species (ROS) plays a critical role in IH-evoked changes in neonatal carotid bodies. Experiments were performed on neonatal rats exposed either to 10 days of IH (P0-P10; 8 h/day) or to normoxia. IH augmented HSR of the carotid bodies ex vivo and resulted in hyperplasia of glomus cells. The effects of IH were associated with enhanced basal release of ET-1 under normoxia, sensitization of carotid body response to exogenous ET-1, and upregulation of ET(A) but not an ET(B) receptor mRNA without altering the ET-1 content. An ET(A) but not ET(B) receptor antagonist prevented augmented HSR by IH. ROS levels were elevated in carotid bodies from IH-treated rat pups as evidenced by increased levels of malondialdehyde. Systemic administration of manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 5 mg/kg ip), a scavenger of O(2)(*-), prevented IH-induced elevation of ROS, basal release of ET-1, upregulation of ET(A) mRNA, and augmented HSR. In striking contrast, MnTMPyP treatment had no significant effect on IH-induced hyperplasia of glomus cells. These results demonstrate that IH-evoked increase in HSR involve a ROS-mediated increase in basal ET-1 release and upregulation of ET(A) receptor mRNA.
    AJP Regulatory Integrative and Comparative Physiology 01/2009; 296(3):R735-42. · 3.28 Impact Factor
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    ABSTRACT: Previous studies suggest that carotid body responses to long-term changes in environmental oxygen differ between neonates and adults. In the present study we tested the hypothesis that the effects of chronic intermittent hypoxia (CIH) on the carotid body differ between neonates and adult rats. Experiments were performed on neonatal (1-10 days) and adult (6-8 wk) males exposed either to CIH (9 episodes/h; 8 h/day) or to normoxia. Sensory activity was recorded from ex vivo carotid bodies. CIH augmented the hypoxic sensory response (HSR) in both groups. The magnitude of CIH-evoked hypoxic sensitization was significantly greater in neonates than in adults. Seventy-two episodes of CIH were sufficient to evoke hypoxic sensitization in neonates, whereas as many as 720 CIH episodes were required in adults, suggesting that neonatal carotid bodies are more sensitive to CIH than adult carotid bodies. CIH-induced hypoxic sensitization was reversed in adult rats after reexposure to 10 days of normoxia, whereas the effects of neonatal CIH persisted into adult life (2 mo). Acute intermittent hypoxia (IH) evoked sensory long-term facilitation of the carotid body activity (sensory LTF, i.e., increased baseline neural activity following acute IH) in CIH-exposed adults but not in neonates. The effects of CIH were associated with hyperplasia of glomus cells in neonatal but not in adult carotid bodies. These observations demonstrate that responses to CIH differ between neonates and adults with regard to the magnitude of sensitization of HSR, susceptibility to CIH, induction of sensory LTF, reversibility of the responses, and morphological remodeling of the chemoreceptor tissue.
    Journal of Applied Physiology 06/2008; 104(5):1287-94. · 3.48 Impact Factor
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    ABSTRACT: Chronic intermittent hypoxia (CIH) is associated with recurrent apneas in adults and premature infants. It has been proposed that reflexes arising from the carotid bodies contribute to the autonomic abnormalities associated with CIH. The purpose of this review is to summarize recent studies on the effects of CIH on adult and neonatal carotid bodies. CIH exerts two major effects on the adult carotid body that includes sensitization of the hypoxic sensory response and induction of sensory long-term facilitation (LTF). In neonates CIH leads to sensitization of the hypoxic response but does not induce sensory LTF. The effects of CIH on carotid bodies develop over time and could be reversed in adults but not in neonates. CIH-evoked changes in the carotid body involve reactive oxygen species (ROS)-mediated signaling and transcriptional activation by hypoxia-inducible factor-1. Augmented chemoreceptor sensitivity to hypoxia increases the likelihood of unstable breathing perpetuating the effects of CIH, whereas sensory LTF may contribute to increased sympathetic tone and systemic hypertension associated with recurrent apneas.
    Respiratory Physiology & Neurobiology 08/2007; 157(1):148-53. · 2.05 Impact Factor